Aliskiren improves insulin resistance and ameliorates diabetic vascular complications in db/db mice
Aliskiren improves insulin resistance and ameliorates diabetic vascular complications in db/db mice
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DOI：
10.1093/ndt/gfq579
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发表时间：
2011-04-01
影响因子：
6.1
通讯作者：
Cha, Dae Ryong
中科院分区：
文献类型：
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作者：
Kang, Young Sun;Lee, Mi Hwa;Cha, Dae Ryong
背景。阿利吉仑是一种直接肾素抑制剂 (DRI)，在人体和动物实验中具有器官保护作用。然而，目前没有证据表明DRI对2型糖尿病动物的胰岛素抵抗和代谢异常有影响。方法。我们研究了阿利吉仑对 db/db 小鼠和培养的系膜细胞 (MC) 的作用和分子机制。结果。通过微型渗透泵以 25 mg/kg/天的剂量进行阿利吉仑治疗 3 个月，并未引起血糖水平、收缩压、血清肌酐和电解质水平的显着变化。然而，经胰岛素耐量试验和各种生物标志物（包括稳态模型评估指数水平和脂质异常）证实，阿利吉仑治疗改善了胰岛素抵抗。治疗组还表现出心脏功能和形态异常的显着改善，包括左心室肥厚和脂肪组织的诱导表型变化。阿利吉仑治疗还显着减少尿白蛋白排泄、肾小球硬化，抑制促纤维化和促炎细胞因子的合成，并改善肾脂质代谢。在培养的 MC 中，高葡萄糖刺激增加了 MC 肾素浓度。此外，肾素治疗直接上调促炎和促纤维化细胞因子的合成，而先前使用阿利吉仑和血管紧张素受体（AT1）拮抗剂治疗可消除这些细胞因子的合成。这些结果表明阿利吉仑的有益作用是通过血管紧张素依赖性机制介导的。结论。总之，这些结果表明阿利吉仑通过改善胰岛素抵抗和脂质异常来提供器官保护作用，以及对 db/db 小鼠靶器官的直接抗纤维化作用。阿利吉仑可能是治疗2型糖尿病和糖尿病肾病的有用的新治疗药物。
Background. Aliskiren is a direct renin inhibitor (DRI) and provides an organ-protective effect in human and animal experiments. However, there is no current evidence of the effect of DRI on insulin resistance and metabolic abnormalities in type 2 diabetic animals.Methods. We investigated the effects and molecular mechanism of aliskiren in db/db mice and cultured mesangial cells (MCs).Results. Aliskiren treatment for 3 months at a dose of 25 mg/kg/day via an osmotic mini-pump did not induce significant changes in blood glucose levels, systolic blood pressure, serum creatinine and electrolyte levels. However, aliskiren treatment improved insulin resistance confirmed by insulin tolerance test and various biomarkers including homeostasis model assessment index levels and lipid abnormalities. The treated group also exhibited significant improvement in cardiac functional and morphological abnormalities including left ventricular hypertrophy, and induced phenotypic changes in adipose tissue. Aliskiren treatment also markedly decreased urinary albumin excretion, glomerulosclerosis and suppressed profibrotic and proinflammatory cytokine synthesis and improved renal lipid metabolism. In cultured MCs, high glucose stimulation increased MC renin concentration. Furthermore, renin treatment directly up-regulates synthesis of proinflammatory and profibrotic cytokines, which were abolished by prior treatment with aliskiren and angiotensin receptor (AT1) antagonist. These results suggest that the beneficial effect of aliskiren is mediated by an angiotensin-dependent mechanism.Conclusions. Together, these results imply that aliskiren provides an organ-protective effect through improvement in insulin resistance and lipid abnormality, as well as direct anti-fibrotic effect in target organ in db/db mice. Aliskiren may be a useful new therapeutic agent in the treatment of type 2 diabetes mellitus and diabetic nephropathy.